Understanding the natural history of human papillomavirus (HPV) infection throughout the female life span will be critical in guiding future cervical cancer prevention programs, including screening and HPV vaccination. Age-specific trends of HPV prevalence show a second peak of HPV among older women in some populations. Few studies have been conducted to understand this observation, and historical cohorts will be of little value for further investigation. Women currently reaching the age of menopause in the US have experienced different risks throughout their lifetime due to the strong cohort effects that resulted from the sexual revolution that occurred in the 1960s and 1970s. It is therefore imperative to study contemporaneous cohorts of women through the menopausal transition to gain an understanding of the natural history of HPV infection in later life, including the risk of new HPV infections, reactivation of previously acquired infections, and persistence and disease progression of either reactivated or newly acquired infection. We propose to conduct a prospective cohort study of 1500 women belonging to the 1945-1965 'baby boomer' birth cohort to accomplish the following specific aims: (1) To compare the prevalence, (2) incidence, and (3) duration of HPV infection and squamous intraepithelial lesions (SIL) in pre-, peri-, and post-menopausal women, and (4) to estimate the minimum fraction of incident HPV DMA detection and seroconversion associated with reactivation vs. new sexual exposures. We will enroll a racially and socioeconomically diverse cohort in Baltimore, Maryland and follow the women for HPV and SIL every four months over a two year period. Our observational data will be supported by detailed molecular epidemiologic characterization of the viral infection (viral load, variant status, and gene expression) and the host response (cervical cytokine expression) among women with persistent vs. resolving infections. The successful completion of the study will provide stable estimates of risk of new HPV detection and SIL as a function of menopausal transitions and sexual exposures vs. reactivation in a contemporaneous cohort of aging women with the US. This information will be critical for development of cost-effective cervical cancer prevention policies. The complementary molecular studies will add important biological information that may lead to new approaches in screening and treatment of cervical HPV infections and neoplasia.